The present invention relates to a medicine for the prevention and treatment of neurodegenerative diseases comprising a 5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivative or a physiologically acceptable acid addition salt thereof as an active ingredient, and use of said compound for the manufacture of a medicine for the prevention and treatment of neurodegenerative diseases.
With developing into an aging society, the number of patients suffering from neurodegenerative diseases such as Alzheimer""s disease is increasing. Alzheimer""s disease is a progressive neurodegenerative disorder of the central nervous system which symptoms are mainly attenuation and decline of memory, and it is suggested by the neurochemical studies that the main cause is dysfunction of neurotransmissions in plural neurotransmitter systems such as acetylcholine, xcex3-aminobutyric acid (GABA), glutamic acid, and dopamine. On the basis of the finding that the neuronal dysfunction occurs remarkably in cholinergic system among those systems, a medicine has been developed for the purpose of improvement in cognitive deficits by means of the activation of cholinergic system.
Besides, there are also some attempts to develop benzodiazepine (BZP) receptor inverse agonists as the therapeutic agent for treatment of dementia. Heretofore, many studies have been done on the relationship between the binding-manner to the BZP receptor and the pharmacological activity, and in view of the pharmacological activity thereof, BZP agonists have been used as antianxiety drugs (e.g. diazepam), as hypnotics (e.g. triazolam), or as antiepileptic drugs (e.g. clonazepam). However, it is well-known that administration of BZP agonists causes amnesia (amnesic action) as a side effect. On the other hand, since it is known that BZP inverse agonists exhibit the actions opposite to those of BZP agonists, and enhance cholinergic activity which is considerably related with cognitive function, the inverse agonist is expected to have the anti-dysmnesia action (anti-amnesia action) and to activate cerebral function.
As an example of such a compound, WO 99/03857 discloses 5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivatives of the following formula: 
wherein Het is an oxadiazolyl group;
R1 is a hydrogen, a lower alkyl group, a cyclo-lower alkyl group, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, etc.; and
R2 is a hydrogen, a lower alkyl group, a cyclo-lower alkyl group, a substituted or unsubstituted aryl group, etc.,
in which it is described that said compounds exhibit selective and high affinity to benzodiazepine receptor and are useful as benzodiazepine receptor ligands, especially as inverse agonists, which are expected to be cerebral activators or therapeutic agents for treatment of senile dementia and Alzheimer""s disease.
Recently, it has been indicated that schizophrenia and Alzheimer""s disease are related with the hypofunction of ion-channel type N-methyl-D-aspartic acid (hereinafter, abbreviated to xe2x80x9cNMDAxe2x80x9d) receptor, which is a subtype of glutamic acid receptors. Phencyclidine, a noncompetitive antagonist of NMDA receptor, exhibits excellent pharmacological activities such as anesthetic activity and neuroprotective activity for acute encephalopathy, while it has been ever used for the undesirable purpose of extensive drug abuse as street drug. After E. D. Luby et al. reported that phencyclidine caused schizophrenia-like hallucination and mental aberration in human beings [Archives Neurology and Psychiatry. Vol 81, pp 363-369 (1959)], a lot of studies thereof have been accumulated until today. It has been proved that phencyclidine causes schizophrenia-like hallucination and mental aberration in human beings more strongly than amphetamine or LSD (9,10-didehydro-N,N-diethyl-6-methyl-ergoline-8xcex2-carboxamide). Additionally, in the case of animals, it is known that NMDA receptor antagonists such as phencyclidine, MK-801 (dizocilpine maleate: (+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate) and ketamine, cause the enhancement of spontaneous motor activity and aberrant behaviors related with the symptoms of mental aberration such as hallucination, as well as ataxia, and such behavioral changes are suppressed by medicines for schizophrenia (e.g. haloperidol, risperidone and olanzapine), antianxiety drugs (e.g. diazepam), and antagonists of NMDA receptor glycine site (e.g. HA-966: R(+)-3-amino-1-hydroxy-2-pyrrolidinone). It is also known that NMDA receptor antagonists (MK-801, phencyclidine and ketamine) cause learning/memory disorder in animals. Consequently, a medicine suppressing hypofunction of NMDA receptor is expected to be useful for therapy of dysmnesia and schizophrenia.
It is known that MK-801 is a noncompetitive antagonist for NMDA receptor, which is a subtype of glutamate receptors, and encephalic neuronopathy (leading to cell death via cell vacuolization) is caused by the systemic administration of said agent to animals. That is, in the case of the single application of MK-801 at moderate doses (0.3-1.0 mg/kg), neuronal vacuolization is observed in the posterior cingulate (PC)/retrosplenial cortex (RS) (hereinafter, abbreviated to PC/RS cortex) in 4-5 hours after administration, and in the case of higher doses (3-10 mg/kg), necrosis of neurons and hyperplasia of glial cells are observed in a few days to a few weeks after administration. Besides, in the case of repeated application, the damage spreads to hippocampal ventral dentate gyrus and limbic regions such as entorhinal cortex and amygdala. It is presumed that the hypofunction of NMDA receptor may cause neurodegeneration in the PC/RS cortex through complicated polysynaptic network mechanism [in which at least 7 receptors, i.e. glutamic acid (NMDA and non-NMDA), acetylcholine-M3, adrenaline-xcex12, GABA-A, sigma and serotonin 2A, are involved], since such neurodegeneration would be caused by both noncompetitive antagonists of NMDA receptor (phencyclidine and ketamine) and competitive antagonists [e.g. D-2-amino-5-phosphono-pentanoic acid (D-AP5)]. It is considered that the dysfunction of NMDA receptor caused by administration of MK-801 may be closely related to the onset of neurodegenerative diseases, and hence the neuronopathy induced by MK-801 will be usable as a pathological model of neurodegenerative diseases [see, G. Ellison. Brain Research Reviews. Vol 20, pp 250-267 (1995); D. F. Wozniak et al., Brain Research. Vol 707, pp 165-179 (1996); J. W. Olney et al., J. Psychiatric Research. Vol 33, pp 523-533 (1999); P. Andine et al., J. Pharmacol. Exp. Ther., Vol 290, pp 1393-1408 (1999)].
It is known that medicines inhibiting MK-801-induced neuronopathy include anticholinergic drugs (e.g. scopolamine and atropine), barbiturate hypnotics (e.g. pentobarbital and thiopental), and benzodiazepine derivatives (e.g. diazepam) [see, J. W. Olney et al., Science, Vol 254, pp 1515-1518 (1991)].
The present inventors have found that 5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivatives of the formula (I) or physiologically acceptable acid addition salts thereof exhibit an extremely potent inhibitory effect on the MK-801-induced neurodegeneration in the PC/RS cortex by using the above pathological model.
An object of the present invention is to provide a medicine for the prevention and treatment of neurodegenerative diseases comprising a 5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivative of the following formula (I): 
wherein:
Het is an oxadiazolyl group;
R1 is a hydrogen atom, a lower alkyl group, a cyclo-lower alkyl group, a trifluoromethyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkoxy-lower alkyl group, a hydroxy-lower alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; and
R2 is a hydrogen atom, a lower alkyl group, a cyclo-lower alkyl group, a cyclo-lower alkylmethyl group, a lower alkenyl group, a cyclo-lower alkenyl group, a lower alkynyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or a physiologically acceptable acid addition salt thereof.
Another object of the present invention is to provide use of a 5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivative of the formula (I) or a physiologically acceptable acid addition salt thereof for the manufacture of a medicine for the prevention and treatment of neurodegenerative diseases.
A further object of the present invention is to provide a method for the prevention and/or treatment of neurodegenerative diseases in mammals (including human beings), which comprises administering an effective amount of a 5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivative of the formula (I) or a physiologically acceptable acid addition salt thereof to said mammals in need of such prevention and/or treatment.